title: Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.
abstract: Elevated expression of p130Cas (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. p130Cas is a downstream target of the tyrosine kinase c-Src. Signaling mediated by p130Cas through its phosphorylated substrate domain (SD) and interaction with effector molecules directly promotes tumor progression. We previously developed a constitutively phosphorylated p130Cas SD molecule, Src*/SD (formerly referred to as Src*/CasSD), which acts as decoy molecule and attenuates the transformed phenotype in v-crk-transformed murine fibroblasts and human breast cancer cells. To test the function of this molecule in vivo, we established mouse mammary tumor virus (MMTV)-long terminal repeat-Src*/SD transgenic mice in which mammary gland development and tumor formation were analyzed. Transgenic expression of the Src*/SD molecule under the MMTV-long terminal repeat promoter did not interfere with normal mammary gland development or induce tumors in mice observed for up to 11 months. To evaluate the effects of the Src*/SD molecule on tumor development in vivo, we utilized the MMTV-polyoma middle T-antigen (PyMT) murine breast cancer model that depends on c-Src. PyMT mice crossed with Src*/SD mice displayed accelerated tumor formation. The earlier onset of tumors can be explained by the interaction of the Src* domain with PyMT and targeting the fused phosphorylated SD to the membrane. At membrane compartments, it might integrate membrane-associated active signaling complexes leading to increased proliferation measured by phospho-Histone H3 staining. Although these results were unexpected, they emphasize the importance of preventing the membrane association of Src*/SD when employed as decoy molecule.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Yingshe
authors.initials: Y
authors.lastname: Zhao
authors.forename: Joerg
authors.initials: J
authors.lastname: Kumbrink
authors.forename: Bor-Tyh
authors.initials: BT
authors.lastname: Lin
authors.forename: Amy H
authors.initials: AH
authors.lastname: Bouton
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Toselli
authors.forename: Kathrin H
authors.initials: KH
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D050719:Crk-Associated Substrate Protein / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016391:Genes, src / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics*; D051381:Rats
chemical_list: D050719:Crk-Associated Substrate Protein